Oxygen tension regulates lysosomal proteolysis and RTK level in cancer through mTOR-TFEB-V-ATPase pathway

Authors

• J Hong
• TR Wuest
• Y Min
• PC Lin

Abstract

Oxygen sensing is a fundamental biological process crucial for adaption of living organisms to variable habitats and physiological conditions. The rapid turnover of regulatory molecules in response to extracellular signals is necessary for proper regulation of functional activities, thereby maintaining cellular homeostasis. In this study, we report that oxygen tension regulates activation of lysosomes, the digestive system of the cell. Receptor tyrosine kinase activation by its cognate ligand is known to induce receptor internalization and subsequent degradation in lysosomes. Interestingly, we found that hypoxic conditions, low ambient oxygen concentrations, suppressed lysosomal acidification/activation and receptor degradation via downregulation of vacuolar H+-ATPase, a proton-pump that controls the acidity of lysosomes. Mechanistic analysis showed that hypoxia downregulated mTORc1, reducing its ability to phosphorylate the transcription factor TFEB at S463. Phosphorylation at S463 resulted in the nuclear translocation and activation of TFEB, a master regulator for the expression of the v-ATPase and lysosomal biogenesis. Together, this study presents a novel and essential finding linking oxygen tension to lysosomal activity.

Scientific Focus Area: Cancer Biology

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